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  Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis

Babu, M., Favretto, F., Ibáñez de Opakua, A., Rankovic, M., Becker, S., & Zweckstetter, M. (2021). Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis. Nature Communications, 12: 3396. doi:10.1038/s41467-021-23691-y.

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 Creators:
Babu, M., Author
Favretto, F., Author
Ibáñez de Opakua, A., Author
Rankovic, M.1, Author              
Becker, S.2, Author              
Zweckstetter, M.3, Author              
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for Biophysical Chemistry, Max Planck Society, ou_578571              
2Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
3Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: Amyotrophic lateral sclerosis; Solution-state NMR; X-ray crystallography
 Abstract: Amyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with overlapping clinical features and the pathological hallmark of cytoplasmic deposits of misfolded proteins. The most frequent cause of familial forms of these diseases is a hexanucleotide repeat expansion in the non-coding region of the C9ORF72 gene that is translated into dipeptide repeat polymers. Here we show that proline/arginine repeat polymers derail protein folding by sequestering molecular chaperones. We demonstrate that proline/arginine repeat polymers inhibit the folding catalyst activity of PPIA, an abundant molecular chaperone and prolyl isomerase in the brain that is altered in amyotrophic lateral sclerosis. NMR spectroscopy reveals that proline/arginine repeat polymers bind to the active site of PPIA. X-ray crystallography determines the atomic structure of a proline/arginine repeat polymer in complex with the prolyl isomerase and defines the molecular basis for the specificity of disease-associated proline/arginine polymer interactions. The combined data establish a toxic mechanism that is specific for proline/arginine dipeptide repeat polymers and leads to derailed protein homeostasis in C9orf72-associated neurodegenerative diseases.

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Language(s): eng - English
 Dates: 2021-06-07
 Publication Status: Published online
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41467-021-23691-y
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Title: Nature Communications
Source Genre: Journal
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Pages: 7 Volume / Issue: 12 Sequence Number: 3396 Start / End Page: - Identifier: -